Project Summary/Abstract Acinetobacter baumannii is a highly problematic Gram-negative bacterial pathogen that presents substantial human health and economic burdens. The steady rise in carbapenem-resistance (i.e. imipenem, meropenem) and most recently, polymyxin resistance (i.e., colistin), has led to it being labeled as a ?serious threat? to human health by the CDC. In addition to resistance traits carried on mobile genetic elements, A. baumannii also presents the threat of intrinsic resistance through the production of biofilms, which serve as defensive barriers to existing classes of antibiotics and the host immune response. In 2013, the CDC reported that there were 12,000 Acinetobacter infections in the US, 63% of which were multidrug-resistant (MDR), which resulted in 500 fatalities. However, others have suggested that this number is a gross underestimation, where the real numbers are double or triple what the CDC presented. The most susceptible populations are the elderly and neonates with whom ventilator-associated pneumonia caused by the bacteria have mortality rates >50%. Worldwide, A. baumannii is an even greater problem (~1M infections, ~ 100,000 deaths) especially in Asia, where community-acquired strains have emerged, and infections are not as responsive to treatment. Lastly, pandrug-resistant strains are emerging, and A. baumannii has also been shown to be a reservoir of antibiotic resistance genes for other bacterial species. Therefore, this pathogen places a significant burden on public health. However, A. baumannii infections are also a primary concern of military healthcare, being a common risk to military personnel injured by gunfire and improvised explosive devices. With a limited pipeline of new antibiotics being developed for Gram- negative bacteria (GNB), new therapies are in high demand, especially for this pathogen. We propose to systematically evaluate a one-of-a-kind library of natural products for novel chemical entities (NCEs) that exhibit activity against a panel of MDR-A. baumannii clinical isolates. The innovative nature of this library is due to the fact that it is composed of extracts derived from species (plants and macro-fungi) used in traditional medicine for infectious disease, among other health concerns. The library is highly biodiverse, encompassing >1,200 extracts from over 400 species, derived from 117 families. This project will address two core aims to: 1) Deploy the QNPL drug discovery platform to isolate and identify NCEs that target Acinetobacter baumannii; and 2) Examine suitability of NCE hits for further drug development. Through bringing together experts in natural products chemistry, medicinal chemistry, natural products structure elucidation, A. baumannii pathogenesis and infection models, we are uniquely positioned to undertake the proposed work. Upon completion of these studies, we will be positioned to pursue more in depth preclinical development and medicinal chemistry optimization of lead candidates.